Antibodies against various tumor associated antigens have been widely used in the treatment of different tumors. The emergence of Cetuximab, Trastuzumab and Ipilimumab against solid tumors as well as Rituximab and Ofatumubab against hematological malignancies has highlighted the significant role of antibodies in effective cancer therapy. Trastuzumab and Pertuzumab, which target human epidermal growth factor receptor 2 (HER2) have been shown to synergistically inihibit the growth of HER2 over-expressing breast cancer cells and also kill them. These examples highlight the importance of antibodies in the treatment of tumors as well as the need for identifying more tumor specifc antibodies.
In order to develop tumor specific antibodies, the identity of the target antigens has to be known. Previously described examples of tumor specific antibodies were developed by understanding the basic aspects of tumor biology. For instance, breast tumors that over-express HER2 receptor rely on this signaling pathway for survival and proliferation. Therefore, anti-HER2 receptor antibodies such as Trastuzumab and Pertuzumab were developed to specifically target HER2 over-expressing tumors. Although successful, this targeted approach is limited by our current understanding of tumor biology and does not lead to identification of novel tumor associated antigens.
Humoral immune responses against tumor antigens have been observed in various cancer patients as evidenced by serum antibodies as well as activated B-cells within the sentinel lymph nodes. In previous studies, a unique strategy was developed to identify novel tumor associated antigens. The strategy involved identification of activated and proliferating B-cells within the sentinel lymph nodes of breast cancer patients. Without being held to theory, it was hypothesized that these B-cells could be activated by unique antigens derived from the tumor. Therefore, analyzing antibodies produced by these B-cells could lead to the identification of tumor associated antigens. Previously, cDNA molecules of variable heavy chain domains were generated from the activated B-cells. cDNA molecules that were part of clonal groups as well as exhibited somatic hypermutation within the complementarity determining regions were selected and sequenced. In the indexed study, single domain antibodies from the activated B-cells were synthesized and screened to identify tumor associated antigens. Using this approach, neuroplastin was identified to be a breast tumor associated antigen that was expressed at high levels in 20% of invasive breast tumors and 50% of those that became metastatic to distal sites. Identification of neuroplastin using these single domain antibodies validated the power of this research strategy to identify novel tumor antigens.
What is needed are additional therapeutic antibodies for the treatment of cancers including late-stage disseminating cancers.